This invention is in the area of organic synthetic chemistry and is in particular a method of preparing a polyanhydride polymer which contains a uniform distribution of aliphatic and aromatic residues for use as a bioerodible matrix material for controlled bioactive compound delivery systems.
Biodegradable controlled release systems for bioactive compounds have an advantage over the other controlled release systems in obviating the need to surgically remove the drug depleted device. The device is implanted under the skin, and degrades during bioactive compound release. Drug loaded devices are generally fabricated by solvent casting, injection molding or compression molding. Injection molding is conducted at temperatures above the melting point of the polymer, and so it is important to construct a polymer which has a melting point lower than the temperature at which drugs begin to degrade or react with the matrix.
Properties of the polymer matrix material other than melting point are very important to obtaining the proper release of the drug. To be useful as a matrix for controlled release of a biologically active substance, the polymer composition must undergo surface erosion in the in vivo environment, rather than bulk erosion. Surface erosion occurs when the rate of hydrolytic degradation on the surface is much faster than the rate of water penetration into the bulk of the matrix. This deters whole scale permeation of the drug molecules into the environment. Bulk erosion occurs when the polymers incorporate water in the center of the matrix, rendering the entire polymer composition sponge like. This results in the break up of the matrix, and creates a channeling effect in which the bioactive compound is released from the matrix. Bulk erosion is directly related to the sensitivity of the polymer composition to hydrolysis. The matrix degrades heterogeneously when it erodes from the surface, and homogeneously when it erodes evenly from the surface and the interior. Polymers which undergo bulk erosion (homogeneous degradation) include polylactic acid, polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers.
The ideal polymer must have a hydrophobic backbone, but with a water labile linkage. Many classes of polymers, including polyesters, polyamides, polyurethanes, polyorthoesters, polyacrylonitriles, and polyphosphazenes, have been studied for controlled delivery applications, but few, except for polyorthoesters, have been designed with these considerations in mind. Leong, K. W., Brott, B. C. and Langer, R., J. Biomed. Mater. Res. 19, 941, 942 (1985). Polyorthoesters, furthermore, erode from the surface only if additives are included in the matrix. Taking advantage of the pH dependence of the rate of orthoester cleavage, preferential hydrolysis at the surface is obtained by either addition of basic substances to suppress degradation in the bulk, or incorporation of acidic catalysts to promote degradation on the surface. Polyanhydrides are well suited as a biodegradable system because they erode in a heterogeneous manner without requiring any such additives.
The degradation products of polyanhydrides are nonmutagenic, noncytotoxic and have a low teratogenic potential, Leong, K. W., D'Amore, P. D., Marletta, M., and Langer, R., J. Biomed. Mater. Res. 20, 51 (1986), which further confirms the utility of these compound for in vivo use.
Polyanhydrides were initially proposed by Hill and Carothers in the 1930s to be a substitute for polyesters in textile applications. Hill, J. J.A.C.S. 52, 4110 (1930); Hill, J.; and Carothors, W. H. J.A.C.S. 54, 1569 (1932). The idea was later rejected because of their hydrolytic instability. It is this property, however, that renders polyanhydrides appealing for controlled release applications. The hydrophilic anhydride linkage ensures biodegradability and may be synthesized with a variety of backbones. It was earlier shown that a model polyanhydride, poly[bis(p-carboxyphenoxy) methane anhydride], displayed near zero-order erosion and release kinetics at 37.degree. and 60.degree. C. Rosen, H. B.; Chang, J.; Wnek, G. E.; Linhardt, R. J.; Langer, R., Bioerodible polyanhydrides for controlled drug delivery, Biomaterials 4, 131 (1983).
Later, three other related compounds, poly 1,3-[bis(p-carboxyphenoxy)propane anhydride] (p(CPP)), the polymer formed from copolymerization 1,3-bis(p-carboxyphenoxy)propane with sebacic acid (p(CPP-SA)), and polyterephthalic acid anyhydride were synthesized and tested for their drug matrix properties. Leong, K. W.; Brott, B. C.; Langer, R., Bioerodible polyanhydrides as drug carrier matrices; J. Biomed. Mater. Res. 19, 941 (1985). The hydrophobic polymers of p(CPP) and p(CPP-SA) (in a 85:15 ratio) displayed constant erosion kinetics over several months, and by extrapolation it was estimated that p(CPP) would completely degrade in over three years. Degradation rates in the range of 10.sup.-1 to 10.sup.-4 mg/h/cm2 were obtained.
Degradation rates were increased significantly by the addition of a compound with more labile anhydride linkages, such as sebacic acid. The compounds which hydrolyze more easily, however, tend to have channeling problems at a stage of about 60% degradation.
Channeling occurs when sufficient anhydride bonds are cleaved in the same region of the matrix that wholescale permeation of the bioactive compound into the environment occurs. For example, in the CPP-SA copolymer, the aliphatic anhydride bonds are cleaved and all drug is released in 10 days (60% degradation), yet the aromatic anhydride regions of the matrix remain for another 51/2 months. See FIG. 1.
The problem that has arisen to date with the use of polyanhydride copolymers as a biodegradable matrix is that if the matrix is very sensitive to hydrolysis, the device absorbs water promoting degradation in the interior of the matrix (homogeneous degradation), which results in a channeling effect. Aliphatic anhydrides in these polymer compositions are more sensitive to hydrolysis than aromatic anhydrides. When aromatic and aliphatic diacids are randomly copolymerized, a non uniform chain structure is obtained which contains regions of aliphatic character, resulting in non uniform degradation and breakup of the matrix.
The problem of bioactive compound channeling in the past was exacerbated by the low molecular weights of the polymers. In Co-pending patent application Ser. No. 892,809, filed Aug. 1, 1986, entitled "Synthesis and Application of High Molecular Weight Polyanhydrides," by Abraham J. Domb and Robert S. Langer, high molecular weight polyanhydrides were formed by melt polycondensation of highly pure isolated prepolymers under optimized reaction conditions, with the optimal inclusion of a catalyst. These higher molecular weight polyanhydrides have improved physico-mechanical properties, however, regions of aliphatic anhydride still present problems of premature release of the drug.
If the polyanhydride is aromatic, although a zero order hydrolytic degradation profile is displayed, the rate of degradation is so slow that the compounds are limited to long-term applications (years). Furthermore, they cannot be fabricated into microspheres or films from solutions because they have low solubility in common organic solvents and have high melting points, which results in the destruction of the drug on preparation of the controlled release device.
It is therefore an object of this invention to provide a method of preparing a polyanhydride polymer composition which degrades uniformly over time in an aqueous medium, and at a rate useful for controlled bioactive compound delivery.
It is another object of this invention to provide a method of preparing a polymer which is soluble in organic solvents and has a low melting point, generally in the range of 40.degree.-100.degree. C., in order to be able to fabricate the controlled release drug device into microspheres or films from solution, or to prepare such compositions by injection molding.